The “Warburg effect” and “glutamine dependency” are two of the most well-known metabolic reprogramming events that occur in cancer cells and distinguish them from many types of normal cells. Normally, glucose is converted to acetyl-CoA, which enters the tricarboxylic acid (TCA) cycle and undergoes oxidative phosphorylation in mitochondria. However, cancer cells convert glucose to lactate even in the presence of oxygen (“Warburg effect”). It was previously thought that the Warburg effect was caused by impaired mitochondrial function in cancer cells. However, recent studies have demonstrated that most cancer cells retain functional mitochondria. Instead of using glucose, most cancer cells utilize glutamine to replenish the TCA cycle. As illustrated in FIG. 1, to enter the TCA cycle, glutamine is first deaminated by glutaminases (GLSs) to generate glutamate. Glutamate is then converted to α-ketoglutarate (α-KG) to replenish the TCA cycle. Three groups of enzymes convert glutamate to α-KG: (1) glutamate pyruvate transaminases (GPTs), (2) glutamate oxaloacetate transaminases (GOTs) and (3) glutamate dehydrogenases (GLUDs). Glutamine metabolites are utilized to produce ATP and synthesize macromolecules, thereby promoting tumor growth. It has long been known that most cancer cells are dependent on glutamine. Although glutamine is a non-essential amino acid, it is nevertheless a required supplement for culturing cancer cells.
Many oncogenes impact glutamine metabolism. Myc overexpression affects glutamine levels by inducing the transcription of GLS1 and the glutamine transporter SLC1A5 (aka ASCT2). In contrast, SLC1A5 expression is repressed by the Rb tumor suppressor, whereas GLS2 was identified as a transcriptional target of p53. In addition, it has been shown that p53 represses the expression of malic enzymes ME1 and ME2, thereby regulating glutamine-dependent NADPH production. A recent study showed that loss of tumor suppressor VHL renders renal cell carcinomas sensitive to glutamine deprivation through HIF-induced metabolic reprograming. Moreover, K-ras up-regulates the aminotransferase GOT1. Though all of these mechanisms impact the production or degradation of glutamine or its metabolites, the reasons that many cancer cells are dependent on glutamine are still unknown or being actively debated.
PIK3CA encodes the catalytic subunit of phosphatidylinositol 3-kinase α (PI3Kα), which plays a key role in regulating cell proliferation, survival and motility. PIK3α consists of a catalytic subunit p110α and one of several regulatory subunits (a major one being p85α). Upon growth factor stimulation, p85 is recruited to phosphorylated receptor protein kinases and adaptor proteins, thereby activating PI3Kα. Activated PI3Kα converts phosphatidylinositol-4,5-biophosphate (PIP2) to phosphatidylinositol-3,4,5-triphosphate (PIP3). The second message PIP3 then activates PDK1 and AKT signaling downstream. PIK3CA is mutated in a wide variety of human cancers.